Colorectal cancer (CRC) is a significant cause of cancer morbidity and mortality affecting almost 150,000 Americans yearly. African Americans have the highest CRC incidence and mortality of all US populations. These disparities have not been explained, and biological risk factors including genetic susceptibility to CRC are understudied in African Americans. I am a gastroenterologist who seeks to develop a career as an independent translational physician-scientist in CRC genetics. My long-term career goals require me to obtain additional training in: 1) molecular and statistical genetics; and 2) cancer biology. The 5-year career development program described in this application will take place at the University of Chicago which distinguishes itself in the field of human and cancer genetics especially in admixed populations. I am fortunate to have key collaborators at the University of North Carolina and the University of Illinois Chicago, and together we have DNA from over 1000 African American CRC patients and 1000 African American control subjects available for my proposed study. Dr. Nancy Cox, Professor of Medicine and Chief of Human Genetics, is my mentor and will provide expertise in statistical genetics. Dr. Nathan Ellis, Associate Professor of Medicine, is a co-mentor and will provide expertise in CRC molecular genetics. An inter-disciplinary Advisory Committee comprised of Dr. Rick Kittles, an expert in genetics of admixed populations, Dr. Olufunmilayo Olopade, an internationally recognized leader in cancer genetics, and Dr. Eugene Chang, a successful physician-scientist in gastroenterology, will guide and advise me during this development period. The broad objectives of this research proposal are the identification of genetic susceptibility factors that contribute to risk of CRC development in African Americans. I will study single nucleotide polymorphisms (SNPs) discovered using genome-wide association studies in European populations. Regions containing these SNP are likely to harbor functional variants. African Americans are an ideal population in whom to identify functional variants because their genomes exhibit less linkage disequilibrium. To this end, I propose three specific aims: 1) Validate candidate CRC-associated regions in African American cases and controls; 2) Discover novel SNPs in CRC-associated regions by targeted resequencing using next-generation sequencing technologies; and 3) Identify putative functional variants in candidate CRC-associated regions that can be further evaluated in future functional studies. By the end of my career development period, I will be uniquely equipped to undertake further translational research in CRC genetics. My long-term research goals are to understand genetic susceptibility in CRC pathogenesis and to study how genetic susceptibility factors can be used to risk stratify individuals for CRC screening and thereby prevent disease especially in high risk but understudied populations like African Americans. PUBLIC HEALTH RELEVANCE: Of all US populations, African Americans have the highest incidence and mortality of colorectal cancer. Reasons for these differences are not explained, and hereditary factors have not been extensively studied in this high risk population. The goal of our study is to better understand hereditary factors that increase risk of colorectal cancer especially in African-Americans.